Mitochondria are cellular organelles found in eukaryotic cells that play a central role in energy metabolism, apoptosis and aging. Mitochondria contain a distinct mitochondrial genome, and human mitochondria (as well as mitochondria of other animals) contain 2 to 10 copies of mitochondrial DNA (mtDNA), which encodes essential components of the oxidative phosphorylation machinery. Proteins encoded by mtDNA are synthesized directly in the mitochondrion. Mitochondrial DNA resembles prokaryotic DNA in that it is a circular, double stranded molecule comprising genes that do not possess introns. The mitochondrion is highly susceptible to mutagenesis, and numerous mtDNA mutations are known to cause disease.
In mammals, the mtDNA encodes 13 proteins of the electron transport chain, 22 transfer RNAs (tRNAs) and two ribosomal RNAs (rRNAs)—12S and 16S rRNAs (Bibb et al., Cell 26:167-180, 1981; Anderson et al., Nature 290:457-465, 1981). There are currently more than 140 known protein-coding mutations affecting endogenous mitochondrial genes, resulting in a myriad of diseases with no current viable therapy. In addition, all of the key components of the electron transport chain are encoded by mitochondria, and electron transport dysfunction has been associated with every major neurodegenerative disease, including Parkinson's disease, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Thus, the ability to modulate mitochondrial function using a gene therapy or an inhibitor mechanism capable of expressing or repressing endogenous mitochondrial genes is desirable.